Project Summary/Abstract C3 glomerulopathy (C3G) is an aggressive form of glomerular disease that occurs at any age and carries the highest risk for irreversible renal failure of the known glomerular diseases. Recurrence post-renal transplant remains a major medical issue for the most patients. This dismal outlook reflects an incomplete understanding of the underlying pathophysiology of C3G, a knowledge gap that has not only led to our inability to explain the limited success of currently available anti-complement agents, but has also hindered the development of new therapies for C3G. Familial cases support the hypothesis that C3G results from primary complement dysregulation however our understanding of the genetics of C3G is incomplete. An adequate accounting for the role of autoantibodies in C3G is also lacking. Finally, in the majority of patients, C3G follows a chronic, indolent course. Activation of the alternative complement pathway can be documented, with kidney biopsies confirming the deposition of complement proteins and their cleavage products in the renal glomerulus. However, the association between complement activity and clinical outcome is poorly understood, a reflection of the absence of longitudinal studies of C3G focused on genetics, autoantibodies, and complement activity in relationship to long-term renal outcome. In this grant, we propose to: ? Specific Aim 1. Define genetic drivers of C3G ? Specific Aim 2. Identify and characterize autoantibodies to complement proteins and convertases ? Specific Aim 3. Develop and validate clinically useful predictive models of disease progression in a longitudinal data-driven analysis of complement factors in C3G Completing these aims will meet our short-term goals, which are to provide a better understanding of C3G and to improve care for C3G patients, and provide a foundation for our long-term goal, which is to identify an effective treatment for this disease.